TY - JOUR
T1 - A PARP1-ERK2 synergism is required for the induction of LTP
AU - Visochek, L.
AU - Grigoryan, G.
AU - Kalal, A.
AU - Milshtein-Parush, H.
AU - Gazit, N.
AU - Slutsky, I.
AU - Yeheskel, A.
AU - Shainberg, A.
AU - Castiel, A.
AU - Seger, R.
AU - Langelier, M. F.
AU - Dantzer, F.
AU - Pascal, J. M.
AU - Segal, M.
AU - Cohen-Armon, M.
N1 - Funding Information:
We thank Dr Liron Miller and Radka Holbova, Sheba Medical Center, for the maintenance of PARP1 KO mice and Efrat Biton in the lab of Prof Menahem Segal, for preparing neuronal cell cultures from PARP1 KO newborn mice. This work was supported by NIH grant 1R21DA027776 and the Israeli Ministry of Health grant (M. C.-A.).
PY - 2016/4/28
Y1 - 2016/4/28
N2 - Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence.
AB - Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence.
UR - http://www.scopus.com/inward/record.url?scp=84964816665&partnerID=8YFLogxK
U2 - 10.1038/srep24950
DO - 10.1038/srep24950
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C2 - 27121568
AN - SCOPUS:84964816665
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 24950
ER -
